Epilepsy is a frequent neurological disorder with a lifetime prevalence of about 2 to 5% that manifests itself in varied forms of epileptic seizures. These seizures range from brief lapses of attention (absence seizures) to limited motor, sensory or psychological changes (partial seizures) to prolonged losses of consciousness with convulsive motor activity (idiopathic or symptomatic generalized tonic clonic seizures). Such symptoms are due to synchronous discharges of large populations of neurons based on a deficit in inhibitory neurotransmission or an excess of excitatory neurotransmission. Current drug therapy cannot completely suppress seizure occurrence in approximately 60% of patients (McNamara, 1994, J. Neurosci. 14:3413-3425). Additionally, therapy is often accompanied by adverse drug effects. Drug resistant forms of epilepsy (most of them mesial temporal lobe epilepsies) require resective surgery of the epileptogenic focus. For many patients, this kind of intervention is a final option that carries an inherent risk of morbidity. Even after surgery, most epileptic patients continue to require antiepileptic drug medication for many years.
Treatment of acute and chronic pain is another serious and unresolved medical problem. In patients with chronic pain, the pain signals are transmitted from the site of pain generation by afferent neurons to the spinal cord. These afferent neurons transmit signal to higher centers in the brain which, upon activation, perceive the pain signal. Frequently, patients with pain syndromes such as neuropathic pain and carcinoma-induced pain do not respond to opiate analgesic drugs and hence their symptoms cannot be treated satisfactorily. Accordingly, millions of patients experience intractable pain.
One compound that has been speculated to be useful for as a drug for inhibiting epileptic activity and pain is adenosine. Adenosine is an endogenous compound with known chemical structure. It occurs naturally in low concentrations in nearly all cells of the body but is normally not released except in some pathological conditions. When adenosine is applied in pharmacological doses to various organ systems in vitro it exerts multiple effects by acting on adenosine receptors (Al and A2). Relatively low systemic doses of adenosine receptor agonists produce marked sedation and hypothermia. At high doses, cessation of spontaneous motor activity as well as some ataxia results. Dunwiddie and Worth, 1982, J. Pharmacol. Exp. Therap. 220:70-76.
In brain tissue in vitro, application of adenosine strongly inhibits neuronal activity (Guieu et al., 1996, Clinical Neuropharmacology 19, 459-474). Neuronal excitation is specifically and potently decreased by adenosine inhibiting the release of excitatory neurotransmitters such as glutamate in a presynaptic, calcium dependent mechanism. Thomson et al., 1993, TINS 16:222-227; Wu and Saggau, 1994, Neuron 12:1139-1148. This effect is mediated via activation of the adenosine A.sub.1 -receptors. Fredholm, 1995, NIPS 10:122-128.
A number of investigators have shown that adenosine and adenosine receptor agonists provide an acute protective effect against epileptic seizures (reviewed in Chin, 1989, Ann. Neurol. 26:695-698; Dragunow, 1988, Progr. Neurobiol. 31:85-108; Foster et al., 1994, Adv. Exp. Med. Biol. 370:427-430; and Greene and Haas, 1991, Progr. Neurobiol. 36:329-341). For example, local microinjection of the adenosine A.sub.1 -receptor agonist cyclohexyladenosine into the brain reduced the duration of convulsions in a kindling model of epileptic seizures. Herberg et al., 1993, Pharmacol. Biochem. Behav. 44:113-117. However, the drug effect was transient and only observed for a time window of 48-72 hours after injection. Many other investigators have found a similar transient effect inhibiting seizure activity after injection of adenosine receptor agonists.
Conversely, long term administration of the adenosine Al analogue CPA i.p. for 9 days actually increased the incidence of chemically-induced seizures precipitated 2 days after termination of CPA injections. Von Lubitz et al., 1994, Eur. J. Pharmacol. 253:95-99. Similarly, Adami and colleagues found that repeated administration of the adenosine Al receptor agonist CCPA resulted in a marked diminution over time of its anticonvulsant effectiveness in a pentylenetetrazole-model of convulsions. Such a reduction in effectiveness was not observed, however, with repeated administration of adenosine A.sub.1 /A.sub.2 receptor agonist NECA, or the adenosine A.sub.2 receptor agonist 2HE-NECA. Adami et al., 1995, Eur. J. Pharmacol. 294:383-389. Since lethal doses of pentylenetetrazole were used by Adami et al., it is unclear whether the lack of tolerance observed during chronic treatment with adenosine A.sub.2 receptor ligands would be maintained in other models of epilepsy.
Adenosine also exerts a powerful antinociceptive action via prejunctional adenosine-receptors in the spinal cord. It has been speculated that adenosine inhibits pain-transducing neurotransmitter signalling. Foster et al., 1994, Adv. Exp. Med. Bio. 370:427-430. In addition, administration of adenosine into peripheral nerve plexus (e.g. plexus axillaris or plexus femoralis) may also inhibit pain. However, adenosine can also induce pain when administered systemically. Presumably, this effect is due to the activation of P2X purinoceptors in the periphery. Sawynok and Sweeney, 1989, Neuroscience 32:557-569.
Accordingly, although transient experiments with adenosine receptor analogs demonstrated a protective effect against seizure activity, long term administration of adenosine receptor agonists may not inhibit seizure activity. Additionally, adenosine receptor agonists exhibited marked adverse effects on the cardiovascular system when administered systemically.